It's not all about the virus—On the importance of modifiable lifestyle factors in the development of hepatocellular carcinoma in chronic hepatitis B
Authors: Mathias Jachs, Hans L. Tillmann
Journal: Hepatology (2022)

Chronic hepatitis B (CHB) infection remains the leading cause of hepatocellular carcinoma (HCC) worldwide. Highly effective antivirals can dramatically reduce the risk for HCC in patients infected with hepatitis B virus (HBV),1 but the risk for HCC development in HBV (and other chronic liver diseases) is also driven by lifestyle and host factors. Modifiable lifestyle factors could be contributing to the recent increase in HCC worldwide after the likely antiviral‐induced initial decline (Figure 1). Several modifiable lifestyle factors have been identified as recently reviewed specifically for NAFLD‐associated HCC2 but are also valid for liver disease in general; these include alcohol use and smoking as risk‐increasing factors and coffee intake, optimized weight, and exercise as risk‐decreasing factors. Although the qualitative association between all these factors and HCC incidence has been previously established, granular data on potential dose‐dependent effects are scarce.FIGURE 1: Annual incidence of HCC based on publicly available data from the Global Burden of Disease Collaborative Network.12In this issue of Hepatology,3 Mak et al. present granular data for diabetes control and smoking in the form of a cohort study conducted in 2330 prospectively characterized Asian patients with CHB, focusing especially on the 671 patients with diabetes within their cohort. Few previous studies have focused on the correlation between optimized diabetes control and the risk for HCC; in fact, only one retrospective study in patients infected with HCV demonstrated the impact of poor diabetes control on increased HCC recurrence following radiofrequency ablation.4 With diabetes known to be a risk factor and some evidence from previous analyses, it was expected that diabetes control would have impact on the risk for HCC; however, this has not been demonstrated as elegantly as in the prospective study by Mak et al. After confirming the presence of diabetes as an independent risk factor for fibrosis progression and HCC in CHB, Mak et al. demonstrate a dose‐dependent relationship between surrogates for glycemic burden, most intuitively the duration of the disease and HbA1c levels at baseline, and the risk for liver cancer during a median follow‐up of almost 6 years and fibrosis progression at 3 years after enrollment. This was independent from liver stiffness and smoking history, two other well‐established risk factors for HCC in various etiologies of chronic liver disease. In turn, the current study has shown that patients who achieved better diabetes control during follow‐up had a numerically lower incidence of HCC, suggesting that rigorous antidiabetic treatment might reduce the risk for adverse outcomes in antivirally controlled CHB, although this remains to be addressed by a longer follow‐up in this cohort and ideally also in specifically designed prospective studies. Focusing on another modifiable lifestyle risk factor for HCC, tobacco smoke is a well‐known, moderately strong risk modifier for HCC in chronic liver disease. Smoking exerts its negative effect partly via the generation of carcinogenic agents in the liver and the induction of proinflammatory cytokines.5 Given the high prevalence of active or current smoking in chronic liver disease, the overall effect size of smoking on the worldwide HCC incidence must not be underestimated. Even worse, smoking has been associated with poorer survival once HCC has developed. On a positive note, it has been demonstrated that former smokers are at a numerically lower risk of developing HCC than current smokers,5 suggesting a positive effect of smoking cessation on HCC development. This is also supported by the data provided in the study by Mak et al., as the authors showed that among patients with CHB and diabetes, smoking promoted hepatocarcinogenesis in a dose‐dependent manner, i.e., the number of pack years smoked had a linear risk‐modifying effect on HCC development in their cohort. Thus, clinicians need to be aware of the deleterious impact of smoking on the natural history of (CHB‐induced) liver disease and address this issue accordingly. Besides investigating potentially modifiable risk factors, Mak et al. also confirmed the well‐established prognostic implications of fibrosis severity/cirrhosis presence on hepatic outcomes in CHB in their cohort. This finding should remind our community that intensified screening programs for HCC according to local recommendations are warranted in patients with advanced fibrosis/cirrhosis. It should further be noted that validated risk scores such as the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH‐B using sex, age, alanine aminotransferase, hepatitis B e antigen, and HBV DNA)6 and PAGE‐B (platelet levels, age, gender)7 models seemed to slightly underestimate the risk for HCC in patients with CHB and (severe) diabetes. Along these lines, some previously proposed scores that include qualitative data on diabetes and/or alcohol use as risk factors for HCC were found to perform well in Chinese as well as European/Canadian patients.8,9 However, it will be worthwhile to explore if incorporating quantitative assessment of lifestyle‐associated host factors into HCC risk prediction models further refines prognostication in future studies. This likely will require network studies and prospective collection of data, taking into account quantitative coffee and alcohol intake and quantitative smoking history. Next‐generation prediction models might also incorporate genetic variants, i.e., single nucleotide polymorphisms, that modulate the risk of HCC development in chronic liver disease.10 The study has some limitations, most importantly the overall relatively low incidence of HCC cases, which for example may explain the lack of sex difference that is usually seen with HCC. Thus, prolonged follow‐up data are eagerly awaited. Second, the initiation of antiviral therapy prior to or after enrollment was up to the treating physician's choice, and thus, some bias by the over‐ or undertreatment of CHB on the effect size of diabetes and smoking cannot be excluded. This might also explain why the strong prognostic implications of pretreatment viral load and other virus‐related risk factors were not confirmed in the current cohort study and that antiviral therapy per se was associated with increased risk of HCC. The latter is likely due to patients with mild HBV‐associated liver disease not being on antiviral therapy. Third, patients consuming alcohol above a sex‐specific threshold of two units for men and one unit for women, respectively, were excluded from the study. However, in addition, the alcohol amount within such limits was not recorded. Thus, the authors could not explore the role of alcohol within their study. This would be an important aspect for future studies in regard to potential safe limits of alcohol use. This is unfortunate because moderate to harmful drinking behavior is common among patients with chronic liver disease, and further insight into the potentially synergistic effects between diabetes, alcohol consumption, and assessment of potential "safe limits" depending on fibrosis stage or disease activity as well as tobacco smoke in CHB are needed. Fourth, data on coffee consumption within this cohort study focusing on lifestyle factors would have been appreciated, as regular consumption of black coffee has been repeatedly demonstrated to have protective effects on hepatocarcinogenesis.11 Lastly, the study was conducted exclusively in Asian patients, and caution is advised when extrapolating its results to cohorts from different regions and ethnities. In conclusion, the insightful study by Mak et al. demonstrates the importance of controlling risk‐modifying lifestyle factors for HCC development and fibrosis progression in CHB. This seems especially important in light of increasing HCC incidences. This study reminds us that crucial risk factors for HCC, especially if modifiable, need to be addressed in each and every patient.